The present invention relates to a liposome pharmaceutical formulation of the compound 6,9-bis-[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate (BBR 2778).
Liposomes are aqueous dispersions of natural and/or synthetic phospholipids (biocompatible and biodegradable) organized in one or more bilayers. When phospholipids are hydrated in aqueous medium, they spontaneously form colloidal micro-particles or carriers, usually of 0.05-5.0 μm of diameter. Liposome particle size ranges from 0.025 μm to 2.5 μm, depending on their structure which can be a single or multiple bilayer structure. The vesicle size is a critical parameter to the determination of liposomes half-life and it affects the volume of the encapsulable medicament.
Liposomes can be classified according to their composition in natural and/or synthetic phospholipids (phosphor-sphingolipids) and their bilayer can further contain other components, such as cholesterol and lipid-conjugated hydrophilic polymers. Depending on their size and number of bilayers, liposomes can also be divided into the following categories: (a) multilamellar vesicles (MLV), (b) large unilamellar vesicles (LUV), (c) small unilamellar vesicles (SUV), (d) multivesicle vesicles (MVV), (e) oligolamellar vesicles (OLV).
The chemical-physical properties of phospholipids which constitute liposomes, such as membrane fluidity, charge density, steric hindrance and permeability, affect the interaction between liposomes and blood components, tissues and cells.
Liposomes are recognizedly to be potentially valuable carriers for medicaments. The capability of liposomes of containing, carrying and releasing medicaments has lead to a number of clinical applications. The simplest use of liposomes in the pharmaceutical field is as non-toxic carriers for insoluble drugs. More complex applications involve the use of liposomes as “reservoirs” for the protracted release of drugs or for the localization of the drug, to either avoid or reach a specific tissue. Drugs in liposome form gave favorable results in the treatment and prevention of a number of diseases, such as in antimicrobial therapy, in anticancer therapy, as adjuvants in vaccines, in hormone and enzyme therapies, in diagnostic techniques and in the treatment of skin and eyes disease. The drugs used in the treatment of diseases such as cancer usually have a restricted therapeutic index and can be highly toxic for normal tissues. A liposome formulation can improve the therapeutic index, modifying the drug biodistribution. Some experiments with liposome-encapsulated anthracyclines with extended plasma half-life have shown a reduction in cardiotoxicity and a better survival of the animals compared with controls, which had been given the free drug. In the case of doxorubicin, an anthraquinone antitumor drug, the use of liposome formulations proved to be effective in reducing toxicity. Doxorubicin most dangerous side-effect is progressive, irreversible heart damage. Liposome-encapsulated doxorubicin showed lower toxicity while maintaining its therapeutic efficacy. U.S. Pat. Nos. 4,797,285, 4,898,735 and 5,043,166 disclose doxorubicin/liposome formulations and the use thereof in the treatment of cancer.